AD is a neurodegenerative disease resulting in the decay of memory and higher cognitive function. Amyloid beta plaques (A-beta), neurofibrillary tangles (NFTs) composed of aggregated tau, neuroinflammation, neuronal dysfunction and degeneration characterize AD, but a unifying theory of pathogenesis including each of these aspects has yet to be identified. There is also a large unmet need in the treatment of this devastating syndrome. The long-term goal of this research is to study the impact of A-beta-induced glial activation on neurons in brain regions affected by AD and to use this information in the development of therapeutics for the treatment of AD. The specific hypothesis for this proposal is that glia activated by Abeta enhance the nitration of tau in neurons and that by blocking glial activation in vivo, tau nitration can be reduced to impede the formation of NFTs. This hypothesis is based on evidence that (a) NFTs are nitrated in AD brain, (b) this nitration is involved in the aggregation of tau, and (c) A-beta is a significant stimulus for the activation of glia, which produce reactive oxygen and nitrogen species that mediate protein nitration. In vitro and in vivo experiments will be used to elucidate the role of glia in tau nitration and NFT formation.